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Original article: Clinical Research SARCOIDOSIS VASCULITIS AND DIFFUSE LUNG DISEASES 2014; 31; 37-45
© Mattioli 1885
Extent of disease activity assessed by 18F-FDG PET/CT in a Dutch sarcoidosis population J.P. Cremers1, M.J. van Kroonenburgh2, R.L. Mostard3, S.A. Vöö2, P.A. Wijnen4, G.H. Koek5, M. Drent1,6 Ild care team, Gelderse Vallei Hospital, Ede; 2Dept. of Radiology and Nuclear Medicine, Maastricht University Medical Centre+ (MUMC+), Maastricht; 3Dept. of Respiratory Medicine, Atrium Medical Centre, Heerlen; 4Dept. of Clinical Chemistry, MUMC+, Maastricht; 5Dept. of Internal Medicine, Division of Gastroenterology and Hepatology, MUMC+, Maastricht; 6Dept. of Toxicology, Faculty of Health, Medicine and Life Sciences (FHML), Maastricht University, Maastricht, The Netherlands 1
Abstract. Background: Sarcoidosis is characterized by a wide range of disease manifestations. In the management and follow-up of sarcoidosis patients, knowledge of extent of disease, activity and severity is crucial. Objectives: The aim of this study was to assess the extent, distribution and consistency of inflammatory organ involvement using 18FFDG PET/CT (PET) in sarcoidosis patients with persistent disabling symptoms. Methods: Retrospectively, sarcoidosis patients who underwent a PET between 2005 and 2011 (n=158) were included. Clinical data were gathered from medical records and PET scans were evaluated. Positive findings were classified as thoracic and/or extrathoracic. Results: Of the studied PET positive sarcoidosis patients (n=118/158; 75%), 93% had intrathoracic activity (79% mediastinal and 64% pulmonary activity, respectively) and 75% displayed extrathoracic activity (mainly peripheral lymph nodes, bone/bone marrow, and spleen). Hepatic positivity was always accompanied by splenic activity, whereas the majority of patients with parotid gland, splenic or bone/bone marrow activity showed lymph node activity. A substantial number of patients with PET positive pulmonary findings (86%) had signs of respiratory functional impairment. No obvious association between hepatic, splenic or bone/bone marrow activity and their corresponding laboratory abnormalities suggestive of specific organ involvement, was found. Conclusions: The majority of studied patients appeared to have PET positive findings (75%), of which a high proportion (75%) displayed extrathoracic activity. Hence, PET can be especially useful in the assessment of extent, distribution and consistency of inflammatory activity in sarcoidosis to provide an explanation for persistent disabling symptoms and/or to provide a suitable location for biopsy. (Sarcoidosis Vasc Diffuse Lung Dis 2014; 31: 37-45) Key words: Fluorine18-fluorodeoxyglucose (18F-FDG), Positron emission tomography/computed tomography (PET/CT), Inflammation, Extrathoracic, Sarcoidosis
Introduction Received: 4 July 2013 Accepted after decision: 13 September 2013 Correspondence: Prof. Dr. M. Drent PO Box 18 6720 AA Bennekom, The Netherlands e-mail address:
[email protected] Phone: +31318434819 Fax: +31 842234007 website: www.maastrichtuniversity.nl, www.ildcare.nl
Sarcoidosis is a multisystemic disease characterized by inflammatory activity with formation of noncaseating granulomas in various organ systems (1, 2). Although the lungs are most commonly affected, no organ is immune to sarcoidosis (3). Sarcoidosis activity can lead to a wide range of disease severity, varying from minimal involvement to derangement of organ
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physiology with functional impairment, such as pulmonary fibrosis or devastating extrapulmonary complications (1, 2, 4-6). Since practically every organ can be involved, patients may present with a wide variety of clinical signs and symptoms (1, 2). Since the clinical course of sarcoidosis is extremely variable, careful assessment of disease extension, severity and activity by organ, with emphasis on vital target organs, is warranted (2, 7). The assessment of inflammatory disease activity is helpful to monitor the course of the disease and guide therapeutic strategies and also in defining endpoints of various disease manifestations for clinical trials (2, 4, 8). An objective system for specific organ assessment to estimate sarcoidosis disease activity, cause and extent, is still lacking. In general, there is no single test or marker available to evaluate specific organ involvement. Each of the currently available markers has its shortcomings and assessment of specific organ involvement may be beyond the scope of the diagnostic tools used (9). A correct estimation of the incidence of organ involvement is therefore, hampered by the difficulty of a reliable confirmation of disease activity for each separate organ. In the ACCESS (A Case Control Etiologic Study of Sarcoidosis) research group study, organ involvement was determined by using an assessment system based on findings from history, physical examination, and laboratory testing (3, 10). In recent years, fluorine18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT or PET) has been shown to be a sensitive method to assess inflammatory activity and the extent of disease in sarcoidosis (11-21). The aim of this retrospective study was to assess the extent, distribution and consistency of organ involvement detected by PET in sarcoidosis patients with persistent disabling symptoms.
Methods Study population The material and methods used in this study have been previously described by our group (18, 19, 22). Between June 2005 and September 2011 a PET was performed in 191/608 sarcoidosis patients referred to the former ild (interstitial lung disease) care
J.P. Cremers, M.J. van Kroonenburgh, R.L. Mostard, S.A. Vöö, et al.
team, a tertiary referral centre of the Department of Respiratory Medicine of the Maastricht University Medical Centre+ (MUMC+) in the Netherlands. The indication for the PET was the presence of unexplained disease related disabling symptoms that persisted for at least one year. Persistent disabling symptoms were defined as the presence of more than one symptom that had substantial influence on quality of life, and that could not be explained with the results of routine investigations, including lung function tests or chest X-rays (CXR). These symptoms included fatigue (Fatigue Assessment Scale (FAS) ≥22) (23), symptoms compatible with small fibre neuropathy (SFN; SFN Screenings List (SFNSL) score ≥11) (24), arthralgia and/or muscle pain, dyspnea (Medical Research Council (MRC) dyspnea scale ≥3), exercise intolerance or cough. Lung function testing and laboratory tests were performed within an interval of less than two weeks of the PET scanning. In the routine workup all patients completed the FAS (23) and the SFNSL (24). Sarcoidosis was proven by the presence of noncaseating granulomas on biopsy according with a compatible clinical picture. Moreover, other causes of granulomatous disease were excluded, according with the consensus statement on sarcoidosis of the American Thoracic Society (ATS)/European Respiratory Society (ERS)/ World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) (1). Exclusion criteria consisted of other diseases that are able to cause PET positive findings. Therefore, five patients with common variable immunodeficiency, five patients with malignancy and one patient with both rheumatoid arthritis and amyloidosis were excluded. Due to an inappropriate interval between PET scanning and obtaining blood samples another 22 patients were excluded. Finally, 158 patients were included. Inflammatory activity was considered to be present in case the PET demonstrated positive findings. Relevant clinical data were gathered retrospectively. This study was approved by the Medical Ethics Board of the MUMC+ (METC 11-4-116) and all patients signed an informed consent. Laboratory tests Serum levels of angiotensin-converting enzyme (ACE), soluble-interleukin2-receptor (sIL2R), Creactive protein (CRP), alanine aminotransferase
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Extent of disease activity assessed by 18F-FDG PET/CT in a Dutch sarcoidosis population
(ALT), and alkaline phosphatase (ALP) were determined as described previously (22). Serum liver test abnormalities (LTA) were defined as being present, if the level of the upper limit of normal times 1.5 was exceeded by ALT (>60 U/L for men and >52.5 U/L for women) and/or ALP (>187.5 U/L for both men and women). Hemoglobin (Hb) level, white blood cell (WBC) count and thrombocyte count were determined on a Sysmex XE-5000 (Sysmex, Hamburg, Germany), according to the manufacturer’s instructions. Lower reference values for Hb were 7.3 mmol/L for the female population and 8.2 mmol/L for the male population; 3.5x109/L for WBC and 150x109/L for thrombocyte count. Pulmonary function tests Forced expiratory volume in 1 s (FEV1) and the forced vital capacity (FVC) were measured with a pneumotachograph (Masterlab, Jaeger). The diffusing capacity for carbon monoxide (DLCO) was measured by the single-breath method (Masterlab, Jaeger, Würzburg, Germany) (25). Values were expressed as a percentage of predicted values (25). Respiratory functional impairment (RFI) was defined as present if FEV1 was
